The present invention relates to new fluorenecarboxylic acid esters of general formula 1
wherein Xxe2x88x92 and the groups A, R, R1, R2, R3, R3xe2x80x2, R4, and R4xe2x80x2 may have the meanings given in the claims and in the description, processes for preparing them and their use as pharmaceutical compositions.
The present invention relates to compounds of general formula 1
wherein:
A denotes a double-bonded group selected from among 
Xxe2x88x92 is an anion with a single negative charge, preferably an anion selected from among chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate;
R denotes hydrogen, hydroxy, methyl, ethyl, xe2x80x94CF3, xe2x80x94CHF2, or fluorine;
R1 and R2, which may be identical or different, denote C1-C5-alkyl which may optionally be substituted by C3-C6-cycloalkyl, hydroxy, or halogen, or
R1 and R2 together denote a xe2x80x94C3-C5-alkylene-bridge; and
R3, R4, R3xe2x80x2, and R4xe2x80x2, which may be identical or different, denote hydrogen, xe2x80x94C1-C4-alkyl, xe2x80x94C1-C4-alkyloxy, hydroxy, xe2x80x94CF3, xe2x80x94CHF2, xe2x80x94CN, xe2x80x94NO2, or halogen.
Preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among 
Xxe2x88x92 denotes an anion with a single negative charge selected from among chloride, bromide, 4-toluenesulfonate, and methanesulfonate, preferably bromide;
R denotes hydroxy, methyl, or fluorine;
R1 and R2, which may be identical or different, denote methyl, ethyl, or fluoroethyl;
R3, R4, R3xe2x80x2, and R4xe2x80x2, which may be identical or different, represent hydrogen, methyl, methyloxy, hydroxy, xe2x80x94CF3, xe2x80x94CHF2, or fluorine.
Particularly preferred compounds of general formula 1 are those wherein
A denotes a double-bonded group selected from among 
Xxe2x88x92 denotes an anion with a single negative charge selected from among chloride, bromide, and methanesulfonate, preferably bromide;
R denotes hydroxy, methyl, or fluorine, preferably methyl or hydroxy;
R1 and R2, which may be identical or different, represent methyl or ethyl, preferably methyl;
R3, R4, R3xe2x80x2 and R4xe2x80x2, which may be identical or different, represent hydrogen, xe2x80x94CF3, xe2x80x94CHF2, or fluorine, preferably hydrogen or fluorine.
Of particular importance according to the invention are compounds of general formula 1 wherein:
A denotes a double-bonded group selected from among 
Xxe2x88x92 denotes bromide;
R denotes hydroxy or methyl, preferably methyl;
R1 and R2, which may be identical or different, represent methyl or ethyl, preferably methyl; and
R3, R4, R3xe2x80x2, and R4xe2x80x2, which may be identical or different, represent hydrogen or fluorine.
The invention relates to the compounds of formula 1 optionally in the form of the individual optical isomers, mixtures of the individual enantiomers, or racemates.
In the compounds of general formula 1 the groups R3, R4, R3xe2x80x2, and R4xe2x80x2, if they do not represent hydrogen, may in each case be arranged in the ortho, meta or para position relative to the bond to the xe2x80x9cxe2x80x94Cxe2x80x94Rxe2x80x9d group. If none of the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 denotes hydrogen, R3 and R3xe2x80x2 are preferably linked in the para position and R4 and R4xe2x80x2 are preferably linked in the ortho or meta position, most preferably in the meta position. If one of the groups R3 and R4 and one of the groups R3xe2x80x2 and R4xe2x80x2 denotes hydrogen, the other group in each case is preferably bonded in the meta or para position, most preferably in the para position. If none of the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 denotes hydrogen, the compounds of general formula 1 wherein the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 have the same meaning are particularly preferred according to the invention.
Also of particular importance according to the invention are those compounds of general formula 1 wherein the ester substituent is in the a configuration on the nitrogen bicyclic group. These compounds correspond to general formula 1-xcex1
The following compounds are of particular importance according to the invention: tropenol 9-hydroxyfluorene-9-carboxylate methobromide; tropenol 9-fluorofluorene-9-carboxylate methobromide; scopine 9-hydroxyfluorene-9-carboxylate methobromide; scopine 9-fluorofluorene-9-carboxylate methobromide; tropenol 9-methylfluorene-9-carboxylate methobromide; and scopine 9-methylfluorene-9-carboxylate methobromide.
The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 5 carbon atoms. Examples include: methyl, ethyl, propyl, or butyl. The groups methyl, ethyl, propyl, or butyl may optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the definitions propyl and butyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl, and tert-butyl, etc.
The alkylene groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, or butylene.
The alkylene-halogen groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably disubstituted, by a halogen. Accordingly, unless otherwise stated, the term alkylene-OH groups denotes branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by a hydroxy.
The alkyloxy groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy, or butyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to by the abbreviations MeO, EtO, PropO, or BuO. Unless otherwise stated, the definitions propyloxy and butyloxy also include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and isopropyloxy, butyloxy includes isobutyloxy, sec-butyloxy, and tert-butyloxy, etc. The word alkoxy may also possibly be used within the scope of the present invention instead of the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy, or butyloxy may optionally also be referred to as methoxy, ethoxy, propoxy, or butoxy.
The alkylene-alkyloxy groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di-, or trisubstituted, preferably monosubstituted, by an alkyloxy group.
The xe2x80x94Oxe2x80x94CO-alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are bonded via an ester group. The alkyl groups are bonded directly to the carbonyl carbon of the ester group. The term xe2x80x94Oxe2x80x94CO-alkyl-halogen group should be understood analogously. The group xe2x80x94Oxe2x80x94COxe2x80x94CF3 denotes trifluoroacetate.
Within the scope of the present invention, halogen denotes fluorine, chlorine, bromine, or iodine. Unless otherwise stated, fluorine and bromine are the preferred halogens. The group CO denotes a carbonyl group.
As explained hereinafter, the compounds according to the invention may be prepared partly analogously to the methods already known in the art (Diagram 1). The carboxylic acid derivatives of formula 3 are known in the art or may be obtained by methods of synthesis known in the art. If only suitably substituted carboxylic acids are known in the art, the compounds of formula 3 may also be obtained directly from them by acid- or base-catalyzed esterification with the corresponding alcohols or by halogenation with the corresponding halogenation reagents. 
As can be seen from Diagram 1, the compounds of formula 2 may be used as starting products for preparing the compounds of formula 1. These compounds are known in the art.
Starting from the compounds of formula 2, the esters of general formula 4 may be obtained by reaction with the carboxylic acid derivatives of formula 3, wherein Rxe2x80x2 denotes, for example, chlorine or a C1-C4-alkyloxy group. When Rxe2x80x2 equals C1-C4-alkyloxy, this reaction may be carried out, for example, in a sodium melt at elevated temperature, preferably at about 50xc2x0 C.-150xc2x0 C., more preferably at about 90xc2x0 C.-100xc2x0 C. at low pressure, preferably at below 500 mbar, most preferably at below 75 mbar. Alternatively, instead of the derivatives 3 wherein Rxe2x80x2 denotes C1-C4-alkyloxy, the corresponding acid chlorides (R is Cl) may also be used.
The compounds of formula 4 thus obtained may be converted into the target compounds of formula 1 by reacting with the compounds R2xe2x80x94X, wherein R2 and X may have the abovementioned meanings. This synthesis step may also be carried out analogously to the examples of synthesis disclosed in WO 92/16528. In the case wherein R1 and R2 together form an alkylene bridge, there is no need to add the reagent R2xe2x80x94X, as will be apparent to one of skill in the art. In this case, the compounds of formula 4 contain a suitably substituted group R1 (for example, xe2x80x94C3-C5-alkylene-halogen) according to the above definitions and the compounds of formula 1 are prepared by intramolecular quaternization of the amine.
Alternatively to the method of synthesizing the compounds of formula 4 shown in Diagram 1, the derivatives 4, wherein the nitrogen bicyclic group denotes a scopine derivative, may be obtained by oxidizing (epoxidizing) compounds of formula 4 wherein the nitrogen bicyclic group is a tropenyl group. According to the invention, the following procedure may be used.
The compound 4 wherein A denotes xe2x80x94CHxe2x95x90CHxe2x80x94 is suspended in a polar organic solvent, preferably in a solvent selected from among N-methyl-2-pyrrolidone (NMP), dimethylacetamide, and dimethylformamide, preferably dimethylformamide, and then heated to a temperature of about 30xc2x0 C.-90xc2x0 C., preferably 40xc2x0 C.-70xc2x0 C. Then a suitable oxidizing agent is added and the mixture is stirred at constant temperature for 2 to 8 hours, preferably 3 to 6 hours. The oxidizing agent is preferably vanadium pentoxide mixed with H2O2, most preferably H2O2-urea complex combined with vanadium pentoxide. The mixture is worked up in the usual way. The products may be purified by crystallization or chromatography depending on their tendency to crystallize.
Alternatively, the compounds of formula 4 wherein R denotes halogen may also be prepared by the method shown in Diagram 2. 
For this, the compounds of formula 4 wherein R denotes hydroxy are converted into the compounds 4 wherein R denotes halogen using suitable halogenation reagents. The method used for the halogenation reactions to be carried out according to Diagram 2 is sufficiently well known in the art.
As is apparent from Diagram 1, the intermediate products of general formula 4 have a central importance. Accordingly, in another aspect, the present invention relates to the intermediates of formula 4
wherein the groups A, R, R1, R3, R3xe2x80x2, R4, and R4xe2x80x2 may be defined as above, optionally in the form of the acid addition salts thereof.
By acid addition salts are meant salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate, preferably the hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate.
As in the compounds of general formula 1 the groups R3, R4, R3xe2x80x2, and R4xe2x80x2, if they do not represent hydrogen, may in each case be arranged in the ortho, meta, or para position relative to the bond of the xe2x80x9cxe2x80x94Cxe2x80x94Rxe2x80x9d group in the compounds of general formula 4 as well. If none of the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 denotes hydrogen, R3 and R3xe2x80x2 are preferably linked in the para position and R4 and R4xe2x80x2 are preferably linked in the ortho or meta position, most preferably in the meta position. If one of the groups R3 and R4 and one of the groups R3xe2x80x2 and R4xe2x80x2 denotes hydrogen, the other group in each case is preferably linked in the meta or para position, most preferably in the para position. If none of the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 denotes hydrogen, the compounds of general formula 4 which are particularly preferred according to the invention are those wherein the groups R3, R4, R3xe2x80x2, and R4xe2x80x2 have the same meaning.
According to the invention, the compounds of formula 4 in the xcex1-configured form are preferably used as the starting materials. These xcex1-configured compounds are therefore of particularly importance according to the invention and correspond to general formula 4-xcex1
In another aspect, the present invention relates to the use of compounds of general formula 2 for preparing the compounds of general formula 4. Moreover, the present invention relates to the use of the compounds of general formula 2 as starting materials for preparing the compounds of general formula 1. Moreover, the present invention relates to the use of the compounds of general formula 4 as an intermediate product in the preparation of the compounds of general formula 1.